Vol 4 n° 4 - Drug Development
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hase 1 studies constitute a pivotal step in drug development.Their goal is to gather enough information to warrant the scientific value of phase 2 studies.The infor- mation  to  be  collected  includes  the  pharmacological actions of the drug, its side effects with increasing doses, its pharmacokinetics (PK) and metabolism, its mechanisms of action, and, if possible, early evidence of effectiveness.1 The classic method of conducting phase 1 studies is much more limited (Table I). First-time-in-man, single-dose, and repeated-dose studies are carried out in healthy volunteers (HV), according to a parallel, double-blind (DB), placebo- controlled design.They are focused on PK, safety, and tol- erability, seeking  the  maximal  tolerated  dose  (MTD), which will be the basis for the choice of doses in subse- 3 7 7 C l i n i c a l   r e s e a r c h Human models as tools in the development of psychotropic drugs Christian Gilles, MD; Therese Schunck, PhD; Gilles Erb, BSc; Izzie Jacques Namer, MD, PhD; Yann Hodé, MD; Jean-François Nedelec, PhD; Peter Boeijinga, PhD; Remy Luthringer, PhD; Jean-Paul Macher, MD Keywords:  drug  development;  proof  of  concept;  model;  healthy  volunteer; Alzheimer’s disease; anxiety; depression; schizophrenia Author  affiliations:  FORENAP,  Institute  for  Research  in  Neuroscience  and Neuropsychiatry, Rouffach, France Address for correspondence: Christian  Gilles,  MD,  FORENAP,  Institute  for Research  in  Neuroscience  and  Neuropsychiatry,  BP  29,  68250  Rouffach, France (e-mail: christian.gilles@forenap.asso.fr) P Despite the growing means devoted to research and development (R & D) and refinements in the preclinical stages, the efficiency of central nervous system (CNS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication and/or in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, tolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound’s pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and phar- macokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase 1 scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R & D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation. Dialogues Clin Neurosci. 2002;4:377-387.